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Mantle Cell Lymphoma: Clinicopathologic Features and Treatments

Mantle Cell Lymphoma: Clinicopathologic Features and Treatments

ABSTRACT: Mantle cell lymphoma (MCL) accounts for approximately 6% of non-Hodgkin’s lymphomas. Patients usually present with advanced disease, with a tendency for extranodal involvement. MCL is an aggressive lymphoma with moderate chemosensitivity, but it remains one of the most difficult therapeutic challenges. Complete response rates to chemotherapy range from 20% to 40%, with median survivals of 2½ to 3 years. Anthracycline-containing regimens do not prolong survival compared with nonanthracycline regimens. Single-agent rituximab (Rituxan) has produced response rates of about 30%, and when combined with an anthracycline-containing regimen, response rates increase to above 90%; however, an impact on survival has not yet been demonstrated. More intensive regimens such as hyperCVAD (hyperfractionated cyclophosphamide [Cytoxan, Neosar], vincristine, doxorubicin [Adriamycin], dexamethasone, methotrexate, cytarabine) with either stem cell transplant or rituximab have been associated with promising results.

The term mantle is derived from
the Latin word mantellum,
which means external covering
or symbol of preeminence. The mantle
zone is the outer covering of the
secondary follicle located in the lymph
node cortex. It engulfs the germinal
center of the secondary follicle and is,
in turn, surrounded by the marginal
zone area. Mantle cell lymphoma
(MCL) was previously called centrocytic
lymphoma or intermediately
differentiated lymphoma and was initially
included in the Working Formulation
along with diffuse small
cleaved-cell lymphoma.[1] With further
characterization of this lymphoma
as a separate entity, its aggressive
behavior became more apparent.[2]

Pathologic and Biologic
Characteristics
Morphology
MCL has several architectural and
cytologic patterns that differ in
their biologic behavior.[3-5] Cytologically,
two main variants are recognized-
typical, or classic, and
blastoid, or blastic (Figure 1). The
typical MCL variant is composed of
small to medium-sized lymphocytes
with scanty cytoplasm, irregular nuclei,
and condensed chromatin. In a
minority of cases, the atypical lymphocytes
may have round nuclei with
little atypia, mimicking chronic lymphocytic
lymphoma, or abundant pale
cytoplasm, mimicking marginal zone
lymphoma.

In the blastoid category, two subgroups
are recognized-classic blastoid
and pleomorphic blastoid. The
classic blastoid variant is characterized
by medium-sized lymphocytes
with scanty cytoplasm and round nuclei
with finely dispersed chromatin
and high mitotic index, resembling
lymphoblasts. The pleomorphic blastoid
variant is composed of heterogeneous
large cells with irregular cleaved
nuclei, finely dispersed chromatin, and
small distinct nucleoli.[5,6]

Architecturally, three different patterns
are recognized in nodes involved
by MCL: mantle zone, nodular, or

diffuse (Figure 2). The mantle zone
pattern (3%-26% of cases) resembles
a normal node with expansion of the
mantle zone with malignant cells. This
pattern is considered a low-grade subtype
of MCL. The nodular pattern
(13%-39% of cases) has ill-defined
follicle-like nodules with neoplastic
cells blending with the nonneoplastic
cells, and germinal centers are absent.
The diffuse pattern (28%-78% of cases)
is composed of small neoplastic

cells replacing the node, with loss of
normal architecture and absent follicles.
The blastoid variant (up to 39%
of cases) often causes a diffuse pattern.[
5] Clinically, it is important to
recognize mantle-zone-pattern MCL
and blastoid MCL.

The incidence of these subtypes of
MCL has varied with different reports.
Histologic progression between the
different patterns is uncommon, although
rare progression from typical
MCL to the blastoid variant has been
documented.[7,8] Bone marrow involvement
is present in more than 50%
of patients with MCL and may be
nodular, diffuse, paratrabecular, or a
combination of these patterns.[9,10]

Immunophenotype
Neoplastic cells in MCL are related
to the mature B-mantle cells of the
follicular lymphoid cuff. These are
monoclonal B cells expressing the Bcell
markers CD19, CD20, CD22,
CD79a, and intense surface immunoglobulin
(Ig)M ± IgD with a tendency
to express more lambda light chain
than kappa light chain. In addition,
the neoplastic cells express CD5,
CD43, Bcl-2, and cyclin D1, and lack
CD10, Bcl-6, and CD23 antigens useful
in differentiating from follicular
lymphoma and chronic lymphocytic
leukemia (Table 1).

Cytogenetics
The t(11;14)(q13;q32) is a characteristic
alteration in MCL. In this translocation,
the heavy-chain joining region
in chromosome 14 is juxtaposed to the
Bcl-1 region on 11q13 (Figure 3). The
CCND1 gene encoding for cyclin D1
is positioned in t(11;14) chromosomal
translocation adjacent to the enhancer
region of the immunoglobulin
heavy-chain gene, resulting in upregulation
of the CCND1 gene (Bcl-1/
PRAD-1) and overexpression of cyclin
D1 protein.[11] Cyclin D1 protein
expression is universal in MCL
and can be detected by immunohistochemical
staining, polymerase chain
reaction (PCR) analysis, or flow cytometry.[
12-14]

Translocation (11;14) is detected
in 65% of MCL cases by classic cytogenetic
analysis, and in nearly all
cases, by fluorescent in situ hybridization
(FISH).[15] Other chromosomal
changes, particularly in blastoid
variants of MCL, include gains in
chromosomes 3q, 8q, and 12q, and
losses in chromosomes 1p, 9p, 11q,
and 13q.[16,17] The ataxia telangiectasia
(ATM) gene has been described
in a few MCL cases with
11q22-23 deletion.[18]

Molecular Biology
Altered apoptosis pathways with
downregulation of the apoptotic genes
FADD, PDCD1, and PAIDD have
been detected by oligonucleotide microarray
in a few MCL patients.[19]
Mutations in p53 and overexpression
of p53 protein occur in blastoid
MCL.[20] The frequency of chromosomal
imbalances and DNA amplifications
are higher in blastoid MCL
than in the common variant.[17]

Cyclin/cyclin-dependent kinase
(CDK) complexes play an essential
role in regulation of cell-cycle progression
through various cell-cycle
checkpoints (cell-cycle-positive regulators).
In MCL, cyclin D1 binds to
CDK4 and forms cyclin/CDK complex,
which binds to the retinoblastoma
protein, leading to its
phosphorylation and the loss of its
suppressor activity on cell-cycle
progression through the release
of transcription factors E2F that
promote cell-cycle progression into
the S phase.[21,22] Mutations in p53
and inactivation of CDK inhibitors
(p16, p18, p21, p27)-both negative
regulators of the cell cycle-have been
reported mostly in the aggressive variants
of MCL.[20] Proteosome activity
might be responsible for the
degradation of some of these CDK
inhibitors.[23]

Differential Diagnosis of MCL
MCL has been confused with other
lymphomas due to morphologic
similarities (Table 1). Nodular MCL
with residual germinal centers may
be morphologically similar to follicular
lymphomas. However, follicular
lymphomas are usually CD5-negative,
CD43-negative, Bcl-6-positive, and
CD10-positive, whereas MCL is the
opposite. Both MCL and marginal
zone lymphomas have a tendency to
involve the gastrointestinal tract and
bone marrow. Marginal zone lymphomas
are usually CD5-negative and
cyclin D1-negative. Small lymphocytic

lymphoma/chronic lymphocytic
leukemia may resemble MCL morphologically.
However, although both
are CD5-positive and CD43-positive,
usually small lymphocytic leukemia/
chronic lymphocytic leukemia is
CD23-positive and MCL is CD23-
negative. Blastoid MCL might also
be confused with lymphoblastic lymphoma,
which is terminal deoxynucleotidyl
transferase (TdT)-positive.

Immunophenotype, cytogenetics,
FISH, and flow cytometry are sensitive
and useful tools for identifying
t(11;14)(q13;q32) and cyclin D1 overexpression-
both of which are characteristic
of MCL-in tissue obtained
from tumor sites and bone marrow
biopsies.

Clinical Presentation of MCL
MCL is diagnosed at a median age
of 60 years, with a male-to-female
ratio of 4:1 (Table 2). Patients usually
present with advanced disease. Approximately
60% of patients fall into
the intermediate-prognostic group (International
Prognostic Index 2/3). The
incidence of generalized lymphadenopathy
is about 70%, and of B symptoms,
30%. Lactate dehydrogenase
and beta-2-microglobulin levels are
elevated in about 50% of patients.

Bone marrow involvement is common
and occurs in about 60% of patients,
irrespective of peripheral blood
involvement. Lymphocytosis and peripheral
blood involvement occurs in
30% of cases, and extranodal involvement
in more than one site, in about
10% of patients. The most common
sites of extranodal involvement are
the spleen, liver, and gastrointestinal
tract. Extensive lymphomatous polyposis
involvement of the bowel can
occur, although nonmacroscopic involvement
is more common. Central
nervous system involvement is more
common in blastoid MCL.[4,24-26]

Prognostic Factors and Outcome
Tumor-associated prognostic features
are mainly related to the morphologic
pattern (Table 3). The mantle
zone variant has an indolent behavior
similar to that of low-grade lymphomas,
while the blastoid variant has an
aggressive clinical behavior.[25,27]
High mitotic index and elevated Ki-
67 index have also been correlated
with poor outcome.[27-29] Peripheral
blood involvement at diagnosis predicts
poor outcome, whereas bone
marrow involvement does not.[10]
In one small study, no difference
in survival was seen between patients
with t(11;14) and those with no
detected translocation.[27] Mutations
in p53 and abnormalities in the
CDK inhibitors p16 and p21 are usually
associated with aggressive
MCL.[30,31] Mutated VH genes and
low CD38 expression are described
in a subset of mantle cell lymphoma
with an indolent course.[32] Older
age, male sex, poor performance status,
B symptoms, advanced disease
at presentation, lymphocytosis, elevated
beta-2-microglobulin, and splenomegaly
are also poor prognostic
factors.[33]

TreatmentChemotherapy
Since MCL was first recognized
as a separate disease entity, response
rates and overall survival have been
noted to be poor. Fisher et al reported
the results of a Southwest Oncology
Group study designed to determine
the natural history of patients with
MCL and marginal zone lymphoma
treated with the CHOP regimen (cyclophosphamide
[Cytoxan, Neosar],
doxorubicin HCl, vincristine [Oncovin],
prednisone) between 1972 and
1983.[34] The failure-free survival
was significantly shorter for the 36
MCL patients compared to the 348
remaining patients. The 10-year failure-
free survival estimate for MCL
patients was only 6%, compared to
25% for patients with other indolent
lymphomas.

Multiple chemotherapeutic regimens
have been tested, but none has
demonstrated a clear superiority
(Table 4).[33-61] Reported overall response
rates range from 30% to 90%,
and complete response rates, from
10% to 90%.[35-38] Despite large
differences in reported overall response
rates, overall survival has remained
essentially the same across
many of the studies (range: 24 to 60
months).[4,8,33-46]

  • Role of Anthracyclines-Several
    randomized clinical trials comparing
    anthracycline-containing to non-
    anthracycline-containing regimens
    have been reported.[38,39,52] In 1989,
    Meusers et al reported the first randomized
    clinical trial in MCL to
    compare COP (cyclophosphamide,
    vincristine, prednisone) to the more
    aggressive anthracycline-containing
    regimen CHOP in 63 newly diagnosed
    patients.[38,39,52] No significant difference
    was found between those treated
    with COP vs those treated with
    CHOP with respect to complete response
    (41% vs 58%), partial response
    (43% vs 31%), relapse rate (73% vs
    67%), relapse-free survival (10 vs 7
    months), or overall survival probability
    (32 vs 37 months).

    A second randomized study by Teodorovic
    et al included data from two
    European Organization for the Research
    and Treatment of Cancer
    (EORTC) Lymphoma Cooperative
    Group trials performed between 1985
    and 1992.[38] In these studies, 64
    MCL patients were treated with four
    different regimens: two intermediategrade
    non-Hodgkin's lymphoma
    (NHL) regimens and two low-grade
    NHL regimens. The intermediategrade
    regimens were CHVmP-VB
    (cyclophosphamide, doxorubicin HCl,
    teniposide [Vumon], prednisone, vincristine,
    bleomycin [Blenoxane]) and
    modified ProMACE-MOPP (prednisone,
    methotrexate, doxorubicin
    [Adriamycin], cyclophosphamide,
    etoposide, mechlorethamine [Mustargen],
    vincristine, procarbazine [Matulane]).
    The low-grade regimen was
    CVP (cyclophosphamide, vincristine,
    prednisone) followed by randomization
    to 1 year of maintenance with
    interferon-alpha or observation. Al-
    though the overall and complete response
    rates were better with the intermediate-
    (83% and 52%) vs the
    low-grade therapy (60% and 40%),
    the median survival was 45 months in
    both treatment arms. In addition, no
    benefit was noted with interferonalpha
    maintenance therapy.

    A third randomized prospective
    study in MCL was conducted by the
    German Low-Grade Lymphoma
    Study Group (GLSG).[52] A total of
    45 patients were randomized to either
    COP or PmM (prednimustine, mitoxantrone
    [Novantrone]) followed by
    a second randomization to interferonalpha
    or observation. The two regimens
    had similar overall response
    rates-COP, 80%, and PmM, 79%-
    although PmM was associated with a
    better complete response rate (27%)
    compared to COP (5%). A significant
    improvement in event-free interval
    was also noted among patients achieving
    a complete response with PmM
    compared to COP-31 vs 14 months.
    However, the estimated median overall
    survival in both treatment arms
    was 28 months.

    These three randomized trials, in
    addition to several nonrandomized trials,
    failed to show improvement in
    overall survival with anthracyclinecontaining
    regimens.[4,33,39,43] In
    contrast, Zucca[41] and Oinonen[37]
    reported a survival advantage among
    patients treated with anthracyclinecontaining
    regimens compared with
    nonanthracycline regimens (CVP or
    single-agent chlorambucil [Leukeran]).

  • Nontraditional Regimens-Other
    investigators have studied regimens
    not traditionally used in the treatment
    of intermediate-grade lymphomas.
    Gressin and colleagues retrospectively
    analyzed data from 30 patients treated
    with the multiple myeloma regimen
    VAD (vincristine/doxorubicin/dexamethasone)
    with or without chlorambucil.[
    44] There was a significantly
    improved complete response rate with
    VAD plus chlorambucil (61%) vs
    VAD (17%). Although these data
    demonstrate the activity of VAD in
    MCL, the results are not significantly
    different from data with CHOP-like
    regimens.

    Decaudin conducted a phase II trial
    of fludarabine (Fludara) in 15 patients
    with relapsed or refractory MCL
    and achieved an overall response rate
    of 33% with no complete responses;
    however, the median overall survival
    was 60 months. Foran et al reported
    improved response rates in a phase II
    trial of fludarabine in newly diagnosed
    MCL patients.[45] The overall
    response rate was 41% (7/17 patients),
    with 5 complete responses, 2 partial
    responses, and a median overall survival
    of 22 months. Other novel agents
    such as flavopiridol (a CDK inhibitor),
    topotecan (Hycamtin), and
    cladribine (Leustatin) have not demonstrated
    activity in MCL.[48,50,51,53]

    Since the choice of chemotherapy
    agent does not appear to have a significant
    impact on outcome in MCL,
    investigators have sought to clarify
    the role of dose intensity. Khouri et al
    demonstrated a survival benefit with
    intensive chemotherapy using hyper-
    CVAD (hyperfractionated cyclophosphamide,
    vincristine, doxorubicin,
    dexamethasone, methotrexate, cytarabine;
    see Table 5) followed by autologous
    stem cell transplant, compared
    to historical controls treated with
    CHOP.[36] HyperCVAD resulted in
    3-year event-free and overall survival
    rates of 92% and 72%, respectively,
    compared to 56% and 28% in control
    patients.

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